The neurohumoral systems and kidneys are closely linked in long-term control of cardiovascular dynamics. Our previous studies provided evidence that abnormal kidney function, manifested by impaired pressure natriuresis, plays a key role in all forms of chronic hypertension studied thus far. Some abnormalities of pressure natriuresis originate intrarenally, but many occur through activation of neurohumoral mechanisms that impair renal excretory capability. For this reason, a major part of our research program has been directed toward understanding the neurohumoral and intrarenal mechanisms that regulate kidney function and how these are altered in chronic hypertension. Our recent work has focused on the mechanisms of obesity hypertension which has special relevance to human essential hypertension. We provided evidence that activation of renal sympathetic nerve activity (RSNA) plays a major role in the pathophysiology of obesityhypertension. We also found that leptin, a cytokine released from adipocytes, contributes to sympathetic nervous system (SNS) activation and increased blood pressure (BP) mainly by stimulating the central nervous system (CMS) pro-opiomelanocortin (POMC) pathway. However, the CMS circuits and cell signaling mechanisms that mediate the chronic effects of the leptin-melanocortin system on RSNA, BP, and metabolism are poorly understood. The central hypothesis of this proposal is that leptin-melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways can differentially and independently regulate appetite, oxygen consumption (VOz) and energy expenditure, RSNA and BP. Specific Aim 1 will determine the role of leptin receptors in the forebrain, POMC and paraventricular (PVN) neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic actions of leptin on control of appetite, V02 and energy expenditure, RSNA, and BP. Specific Aim 2 will determine the specific roles of Stat3, Shp2-MAPK, and lrs2-PI3K signaling in the forebrain, POMC and PVN neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. Specific Aim 3 will determine the role of melanocortin 4 receptor (MC4R) activation in the forebrain and PVN neurons in controlling metabolic and cardiovascular functions, and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. These studies will use novel mouse models in which the leptin receptor or the 3 main leptin signaling pathways (StatS, lrs2-PI3K, and Shp2-MAPK) are deleted by Cre/loxP recombinase in the forebrain, POMC or PVN neurons or in the entire brain to determine the brain regions and cell signaling mechanisms that mediate the chronic actions of leptin, and that constitutively control body weight, total body VO2 and energy expenditure, glucose homeostasis, RSNA and BP. The role of MC4R activation in specific CNS regions in mediating the chronic actions of leptin will be determined in mice with mutated MC4R (loxTB-MC4R'' mice) where the MC4R is rescued in the forebrain, POMC or PVN neurons, or the entire brain. Integrative physiological methods, including 24 hr/day monitoring of BP, RSNA, kidney function, and metabolic functions, in combination with unique genetic models provide a novel and powerful approach to elucidate the complex CNS circuits and signaling pathways by which the leptin-melanocortin system differentially regulates BP, sympathetic activity and metabolic functions that determine energy balance